Analysis of stem-cell associated genes in breast cancer as biomarkers and predictors of cancer malignancy – Dr Adrienne Edkins
Prof Adrienne Edkins
Title of the project
Analysis of stem-cell associated genes in breast cancer as biomarkers and predictors of cancer malignancy.
The aim of this project is to conduct a novel fundamental study to support two clinical needs for breast cancer. These are: (1) the identification of new diagnostic or prognostic markers that correlate with clinical outcome and can therefore be utilized to inform treatment; and (2) the development of more effective treatments against novel targets, particularly in the case of aggressive and metastatic tumours that are over-represented in African communities (such as triple negative breast tumours).
Breast cancer is the most common cancer in women. While there have been advances in breast cancer treatment through the development of new drugs, in most cases, particularly for aggressive or advanced breast cancer, there are few effective treatments. In many cases, early diagnosis and classification of tumours can aid significantly in treatment and cure. One effective way of categorizing breast cancer is to compare the levels of different genes between tumours in order to identify what is known as a ‘genetic expression signature’. If this genetic expression signature can be correlated with the biological responses of the different tumours, it may have prognostic or diagnostic value. This means it may be useful in identifying tumours that may be drug resistant or more aggressive, and therefore support treatment choices. Recent research has suggested that breast cancers, along with other cancers, may develop from a rare population of cancer cells that are biologically different from the majority of the tumour cells. These cancer-initiating cells, known as cancer stem cells, are defined by having stem cell-like characteristics. Stem cells are early undifferentiated cells that are able to divide and differentiate into the range cells of the body. In a similar analogy, cancer stem cells are considered as those cells that can initiate tumour formation, as well as divide and differentiate into all the cells contained within a cancer. This cancer stem cell theory can neatly explain why many cancers are heterogeneous, yet are derived from a single ancestor cell. The cancer stem cell theory further suggests that those cancers associated with stem cell-like characteristics are more aggressive, difficult to treat and more likely to spread. It should therefore be theoretically possible to examine the levels of stem cell associated genes in different breast cancers, to obtain an indication of the response that that cancer will have to treatment, or the likelihood that it will spread and develop a secondary metastasis. Certain types of breast cancer are more likely to be linked with stem cell characteristics. In particular, a highly aggressive and difficult to treat breast cancer, known as the triple negative subtype, has been associated with a high propensity for stem cell characteristics. Interestingly, Southern African women appear predisposed to this triple negative breast cancer, for reasons that are not completely understood. Some studies have been conducted in African American women, but we have little molecular information on the link between stem cell characteristics and breast cancers from indigenous South African populations. Much of what we know about cancers in African populations is derived from studies in African American women, who may share a genetic heritage with Southern African women, but are exposed to substantially different environmental factors.
During our study we will evaluate whether there is a correlation between stem cell characteristics and breast cancer biology. Using cell line models and clinical samples we will evaluate whether the gene profiles we generate might be useful in diagnosis of breast cancer subtypes or clinical outcome, or might inform particular treatment strategies. We will focus on the triple negative breast cancer subtype and will generate population specific data that will aim to enhance our understanding of why indigenous Southern African women are more predisposed to this type of breast cancer. Through this study, we hope to determine whether the cancer stem cell theory of cancer development is relevant in the South African context and to identify new targets for future therapeutic intervention.
Our research project is aimed at understanding how stem cell genes control the biology of triple negative breast cancer (TNBC). TNBC appears to disproportionately affect young black women and is generally considered more difficult to treat due to the lack of defined markers. Stem cell genes are those normally enriched in populations of stem cells (i.e. undifferentiated cells that occur in embryos and tissues and may divide to give rise to other differentiated cells in the body). Our aim is to determine whether stem cell genes are good markers of aggressive TNBC. To do this, we need to understand whether high levels of stem cell genes (such as Oct4 and Sox2) are related to TNBC breast cancers that are more aggressive or difficult to treat. We used validated TNBC cell lines to characterize the link between the stem cell genes and TNBC.
We initially characterized the levels of expression of the stem cell genes in TNBC cell lines and correlated the transcript levels with the clinical history and malignant biology of the cell lines. From this study, we identified the stem cell gene, Oct4, as having a possible relationship with malignant characteristics and therefore we subsequently focused on testing whether we could find a direct relationship between the levels of Oct4 and the malignant characteristics of cells in laboratory studies. In order to complete these studies we required defined systems that would allow us to link the level of Oct4 to biological characteristics. To this end, we established two different model systems that allow us to either increase or decrease the levels of Oct4, relative to a control, and study the effect on the cell’s biology.
The data from these two model studies correlate with each other. That is, when we increase the levels of Oct4 in cells that don’t normally have high levels of the protein, we see an increase in malignancy, particularly with respect to an increase in cell growth. In contrast, when we deplete the levels of Oct4 in cells that naturally express high levels of the protein, we find that the cells grow slower. Together these data suggest that Oct4 may directly regulate cell growth in cancers and the levels of Oct4 may therefore be indicative of a fast-growing tumour. We are awaiting the results from clinical samples, but our data currently suggests that Oct4 may be used as a prognostic marker for aggressive tumours.
- Edkins A Cytotoxic activity of marine sponge extracts from sub-Antarctic Islands and Southern Ocean
- The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells. Aliwaini S., Edkins, A.L., et al. Cancer Letters 357 (2015) 206–218
CHIP: A Co-chaperone for Degradation by the Proteasome. Edkins, A.L.
Hsp90 Co-chaperones as Drug Targets in Cancer: Current Perspectives. Edkins, A.L. 2016.
Cytotoxic activity of marine sponge extracts from the sub-Antarctic Islands and the Southern Ocean. Elisabeth K. Olsen, Adrienne L. Edkins, et al. 2016.
Ferrocenyl and organic novobiocin derivatives: Synthesis and their in vitro biological activity. Mziyanda Mbaba, Adrienne L. Edkins, et al. 2017.
Isolation, Characterization and Antiproliferative Activity of New Metabolites from the South African Endemic Red Algal Species Laurencia alfredensis. Godwin A. Dziwornu, Adrienne L. Edkins, et al. 23 March 2017.
Extracellular Hsp90 and TGFβ regulate adhesion, migration and anchorage independent growth in a paired colon cancer cell line model. Jo-Anne de la Mare, Tamarin Jurgens and Adrienne L. Edkins. BMC Cancer (2017) 17:202.
HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature. Stacey A Mattison & Gregory L Blatch & Adrienne L Edkins. Cell Stress and Chaperones (2017) 22:213–223.